New Etiology for COVID-19: Death results from Immune-Mediation (virus-independent immunopathology: lung and reticuloendothelial system) vs Pathogen-Mediation causing Organ Dysfunction & Hyper-Inflammation – Immunomodulatory Therapeutic Approaches (dexamethasone)
Curators: Stephen J. Williams and Aviva Lev-Ari, PhD, RN
- State of Science on 7/21/2020
New Etiology for COVID-19: Death results from Immune-Mediation (virus-independent immunopathology: lung and reticuloendothelial system) vs Pathogen-Mediation causing Organ Dysfunction & Hyper-Inflammation – Immunomodulatory Therapeutic Approaches (dexamethasone)
Curators: Stephen J. Williams and Aviva Lev-Ari, PhD, RN
- State of Science on 5/19/2020
RNA from the SARS-CoV-2 virus taking over the cells it infects: Virulence – Pathogen’s ability to infect a Resistant Host: The Imbalance between Controlling Virus Replication versus Activation of the Adaptive Immune Response
Curator: Aviva Lev-Ari, PhD, RN – I added colors and bold face
Highlights
- SARS-CoV-2 infection induces low IFN-I and -III levels with a moderate ISG response
- Strong chemokine expression is consistent across in vitro, ex vivo, and in vivo models
- Low innate antiviral defenses and high pro-inflammatory cues contribute to COVID-19
Highlights
- ORF3b of SARS-CoV-2 and related bat and pangolin viruses is a potent IFN antagonist
- SARS-CoV-2 ORF3b suppresses IFN induction more efficiently than SARS-CoV ortholog
- The anti-IFN activity of ORF3b depends on the length of its C-terminus
- An ORF3b with increased IFN antagonism was isolated from two severe COVID-19 cases
Immunomodulatory Therapeutic Approaches (dexamethasone): COVID-19 Death results from Immune-Mediation (virus-independent immunopathology: lung and reticuloendothelial system) vs Pathogen-Mediation causing Organ Dysfunction & Hyper-Inflammation
Highlights
- Dissociation between viral tropism and tissue-spesific immune/inflammatory response
- Inflammatory response only seen in the lungs and reticuloenthothelial system, and not necessarity with viral presence
- No correlation of severity with viral load of RNA fragments and protein presence in serum
Tissue-specific tolerance in fatal Covid-19
Abstract
Successful host defence against a pathogen can involve resistance or tolerance, with implications for prioritising either antimicrobial or immunomodulatory therapeutic approaches. Hyper-inflammation occurs in Covid-19 and is associated with worse outcomes. The efficacy of dexamethasone in preventing mortality in critical Covid-19 suggests that inflammation has a causal role in death. Whether this deleterious inflammation is primarily a direct response to the presence of SARS-CoV-2 requiring enhanced resistance, or an independent immunopathologic process necessitating enhanced tolerance, is unknown. Here we report an aberrant immune response in fatal Covid-19, principally involving the lung and reticuloendothelial system, that is not clearly topologically associated with the virus, indicating tissue-specific tolerance of SARS-CoV-2. We found that
- inflammation and organ dysfunction in fatal Covid-19 did not map to the widespread tissue and cellular distribution of SARS-CoV-2 RNA and protein, both between and within tissues.
- A monocyte/myeloid-rich vasculitis was identified in the lung, along with an influx of macrophages/monocytes into the parenchyma. In addition,
- stereotyped abnormal reticulo-endothelial responses (reactive plasmacytosis and iron-laden macrophages) were present and dissociated from the presence of virus in lymphoid tissues. Our results support
- virus-independent immunopathology being one of the primary mechanisms underlying fatal Covid-19.
- This supports prioritising pathogen tolerance as a therapeutic strategy in Covid-19, by better understanding
- non-injurious organ-specific viral tolerance mechanisms and targeting aberrant macrophage and plasma cell responses.
SOURCE
https://www.medrxiv.org/content/10.1101/2020.07.02.20145003v1
Abstract
Background: Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death.
Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results: 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14).
Conclusions: In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support.
SOURCE
https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1
Other Etiologies Explained
SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19
Reporter: Aviva Lev-Ari, PhD, RN
A mysterious blood-clotting complication is killing coronavirus patients
Once thought a relatively straightforward respiratory virus, covid-19 is proving to be much more frightening
SOURCE
https://www.washingtonpost.com/health/2020/04/22/coronavirus-blood-clots/
Mechanism of thrombocytopenia in COVID-19 patients
Abstract
Since December 2019, a novel coronavirus has spread throughout China and across the world, causing a continuous increase in confirmed cases within a short period of time. Some studies reported cases of thrombocytopenia, but hardly any studies mentioned how the virus causes thrombocytopenia. We propose several mechanisms by which coronavirus disease 2019 causes thrombocytopenia to better understand this disease and provide more clinical treatment options.
Keywords: Severe acute respiratory syndrome coronavirus 2, Coronavirus disease 2019, Thrombocytopenia, Platelet
SAR-Cov-2 is neuro-invasive. Is CNS regulation of peripheral catacholamine outflow disrupted in susceptible patients, CAT leads to platelet aggregation
Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has caused a global pandemic in only 3 months. In addition to major respiratory distress, characteristic neurological manifestations are also described, indicating that SARS-CoV-2 may be an underestimated opportunistic pathogen of the brain. Based on previous studies of neuroinvasive human respiratory coronaviruses, it is proposed that after physical contact with the nasal mucosa, laryngopharynx, trachea, lower respiratory tract, alveoli epithelium, or gastrointestinal mucosa, SARS-CoV-2 can induce intrinsic and innate immune responses in the host involving increased cytokine release, tissue damage, and high neurosusceptibility to COVID-19, especially in the hypoxic conditions caused by lung injury. In some immune-compromised individuals, the virus may invade the brain through multiple routes, such as the vasculature and peripheral nerves. Therefore, in addition to drug treatments, such as pharmaceuticals and traditional Chinese medicine, non-pharmaceutical precautions, including facemasks and hand hygiene, are critically important.
Keywords: coronavirus disease 2019 (COVID-19), SARS-CoV-2, neurological manifestations, neuroinvasion, brain
The neuroinvasive potential of SARS‐CoV2 may play a role in the respiratory failure of COVID‐19 patients
[Correction added on March 17, 2020 after first online publication: Manuscript has been revised with author’s latest changes]
Following the severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV), another highly pathogenic coronavirus named SARS‐CoV‐2 (previously known as 2019‐nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS‐CoV, and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID‐19) with clinical symptoms similar to those reported for SARS‐CoV and MERS‐CoV. The most characteristic symptom of patients with COVID‐19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID‐19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse‐connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. Considering the high similarity between SARS‐CoV and SARS‐CoV2, it remains to make clear whether the potential invasion of SARS‐CoV2 is partially responsible for the acute respiratory failure of patients with COVID‐19. Awareness of this may have a guiding significance for the prevention and treatment of the SARS‐CoV‐2‐induced respiratory failure.
Research Highlights
- SARS‐CoV2 causes epidemic pneumonia characterized by acute respiratory distress.
- This novel coronavirus is similar to SARS‐CoV in sequence, pathogenesis, and cellular entry.
- Some coronaviruses can invade brainstem via a synapse‐connected route from the lung and airways.
- The potential invasion of SARS‐CoV2 may be one reason for the acute respiratory failure.
- Awareness of this will have guiding significance for the prevention and treatment.
Intravascular Platelet Aggregation in the Heart Induced by Norepinephrine
Abstract
Aggregated platelets and occlusive platelet thrombi were found in small myocardial vessels of dogs on electron-microscope examination after prolonged infusion of norepinephrine. The etiology of the myocardial necrosis and fibrosis induced by catecholamines in experimental animals and seen in patients with pheochromocytoma and patients after norepinephrine treatment for shock may be related to this intravascular platelet-aggregating effect of catecholamines. The link between stress and acute myocardial infarction may be via catecholamine-induced intravascular platelet thrombosis. If the thrombogenic theory of atherosclerosis is valid, platelet aggregation induced by catecholamines may be the mechanism whereby arteriosclerotic heart disease is related to stress.
SOURCE
Ramatroban (Baynas®) for the Treatment of COVID-19
Ajay Gupta, MBBS, MD
Department of Medicine,
University of California, Irvine
President & Chief Scientific Officer,
Charak LLC
E-mails:
Off.: 1 (562) 419 7029
Cell: 1 (562) 412 6259
Fax: 1 (702) 974 1001
Multi-Functional Anti-Inflammatory Drugs (MFAIDs) for the Treatment of COVID-19 Patients
Professor Saul Yedgar
Walter & Greta Stiel Chair in Heart Studies
Department of Biochemistry
Hebrew University-Hadassah Medical School
Jerusalem, Israel 91120
Tel: 00972-2-643-9218 (office)
00972-2-652-0159 (home)
Fax: 00972-2-675-7291
Email: yedgar@md.huji.ac.il
Other articles related to the etiology of COVID-19 published in this Open Access Online Scientific Journal include the following:
CORONAVIRUS, SARS-CoV-2 PORTAL @LPBI
http://lnkd.in/ePwTDxm
Launched on 3/14/2020
Eight Pages of LPBI Group’s Coronavirus PORTAL
https://pharmaceuticalintelligence.com/coronavirus-portal/
Lead Curators are:
- Breakthrough News Corner
- Development of Medical Counter-measures for 2019-nCoV, CoVid19, Coronavirus
- An Epidemiological Approach Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN Lead Curators – e–mail Contacts: sjwilliamspa@comcast.net and avivalev-ari@alum.berkeley.edu
- Community Impact Stephen J. Williams, PhD and Irina Robu, PhD Lead Curators – e–mail Contacts: irina.stefania@gmail.com and sjwilliamspa@comcast.net
- Economic Impact of The Coronavirus Pandemic Dr. Joel Shertok, PhD Lead Curator – e–mail Contact: jshertok@processindconsultants.com
- Voices of Global Citizens: Impact of The Coronavirus Pandemic, Gail S. Thornton, M.A. Lead Curator – e–mail Contact: gailsthornton@yahoo.com
- Diagnosis of Coronavirus Infection by Medical Imaging and Cardiovascular Impacts of Viral Infection, Aviva Lev-Ari, PhD, RN Lead Curator e-mail contact: avivalev-ari@alum.berkeley.edu
- Key Opinion Leaders Followed by LPBI Aviva Lev-Ari, PhD, RN and Dr. Ofer Markman, PhD Lead Curators e-mail contacts: oferm2015@gmail.com and avivalev-ari@alum.berkeley.edu
The Castleman Disease Research Network publishes Phase 1 Results of Drug Repurposing Database for COVID-19
Reporter: Stephen J. Williams, PhD.
Corticosteroid, Dexamethasone Improves Survival in COVID-19: Deaths reduction by 1/3 in ventilated patients and by 1/5 in other patients receiving oxygen only
Reporter: Aviva Lev-Ari, PhD, RN – bold face and color fonts added
SARS-CoV-2 is pre-adapted to Human Transmission, branches of evolution stemming from a less well-adapted human SARS-CoV-2-like virus have been found: The Role of SARS-CoV-2 Virus Progenitors for Future Virus Disease Transmission and Pandemic Re-Emergence
Reporter and Curator: Aviva Lev-Ari, PhD, RN – all bold face and colors are my additions
COVID-19: Novel Treatment Protocols using Approved drugs vs Standard of Care vs Vaccine and Antiviral new drug discovery and development – An LPBI Group Response and An LPBI Group & Affiliates Response
Curator: Aviva Lev-Ari, PhD, RN
T cells found in COVID-19 patients ‘bode well’ for long-term immunity | Science | AAAS
https://www.sciencemag.org/news/2020/05/t-cells-found-covid-19-patients-bode-well-long-term-immunity
Clinical Trial for the Use of Nitric Oxide to Treat Severe COVID-19 Infection
RNA from the SARS-CoV-2 virus taking over the cells it infects: Virulence – Pathogen’s ability to infect a Resistant Host: The Imbalance between Controlling Virus Replication versus Activation of the Adaptive Immune Response
Curator: Aviva Lev-Ari, PhD, RN – I added colors and bold face
A Series of Recently Published Papers Report the Development of SARS-CoV2 Neutralizing Antibodies and Passive Immunity toward COVID19
Curator: Stephen J. Williams, Ph.D.
Updated listing of COVID-19 vaccine and therapeutic trials from NIH Clinical Trials.gov
Curator: Stephen J. Williams, PhD
Actemra, immunosuppressive which was designed to treat rheumatoid arthritis but also approved in 2017 to treat cytokine storms in cancer patients SAVED the sickest of all COVID-19 patients
Reporter: Aviva Lev-Ari, PhD, RN
Structure-guided Drug Discovery: (1) The Coronavirus 3CL hydrolase (Mpro) enzyme (main protease) essential for proteolytic maturation of the virus and (2) viral protease, the RNA polymerase, the viral spike protein, a viral RNA as promising two targets for discovery of cleavage inhibitors of the viral spike polyprotein preventing the Coronavirus Virion the spread of infection____________________________ | Curators and Reporters: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN |
Group of Researchers @ University of California, Riverside, the University of Chicago, the U.S. Department of Energy’s Argonne National Laboratory, and Northwestern University solve COVID-19 Structure and Map Potential Therapeutics____________________________ | Curators: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN
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Predicting the Protein Structure of Coronavirus: Inhibition of Nsp15 can slow viral replication and Cryo-EM – Spike protein structure (experimentally verified) vs AI-predicted protein structures (not experimentally verified) of DeepMind (Parent: Google) aka AlphaFold____________________________ | Curators: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN
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